Comparison of ciprofloxacin versus fosfomycin versus fosfomycin plus trimethoprim/sulfamethoxazole for preventing infections after transrectal prostate biopsy.

BACKGROUND: To evaluate antibiotic prophylaxis in transrectal prostate biopsies due to the recommendation of the European Medicines Agency (EMA): We describe our single center experience switching from ciprofloxacin to fosfomycin trometamol (FMT) alone and to an augmented prophylaxis combining fosfomycin and trimethoprim/sulfamethoxazole (TMP/SMX). METHODS: Between 01/2019 and 12/2020 we compared three different regimes. The primary endpoint was the clinical diagnosis of an infection within 4 weeks after biopsy. We enrolled 822 men, 398 (48%) of whom received ciprofloxacin (group-C), 136 (16.5%) received FMT (group-F) and 288 (35%) received the combination of TMP/SMX and FMT (group-BF). RESULTS: Baseline characteristics were similar between groups. In total 37/398 (5%) postinterventional infections were detected, of which 13/398 (3%) vs 18/136 (13.2%) vs 6/288 (2.1%) were detected in group-C, group-F and group-BF respectively. The relative risk of infectious complication was 1.3 (CI 0.7-2.6) for group-C vs. group-BF and 2.8 (CI 1.4-5.7) for group-F vs. group-BF respectively. CONCLUSION: The replacement of ciprofloxacin by fosfomycin alone resulted in a significant increase of postinterventional infections, while the combination of FMT and TMP/SMX had a comparable infection rate to FQ without apparent adverse events. Therefore, this combined regimen of FMT and TMP/SMX is recommended.

Population pharmacokinetic/pharmacodynamic target attainment analysis of IV fosfomycin for the treatment of MDR Gram-negative bacterial infections.

BACKGROUND: IV fosfomycin is used against MDR Gram-negative bacilli (GNB) but has dose-limiting side effects, especially in patients with impaired kidney function. OBJECTIVES: To determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function. METHODS: Adult patients receiving IV fosfomycin for treatment of GNB were eligible. Five serial blood samples were collected after at least three doses of fosfomycin; plasma was assayed by LC-MS/MS and modelled by population pharmacokinetic analysis. The PTA for AUC24/MIC of 98.9 for Escherichia coli and Klebsiella pneumoniae, and 40.8 for Pseudomonas aeruginosa were computed by Monte Carlo simulations. Cumulative fractions of response (CFR) were analysed for each pathogen using EUCAST MIC distributions. RESULTS: A total of 24 patients were included. Creatinine clearance (CLCR) and gender significantly influenced fosfomycin clearance. The kidney function-adjusted dosing regimens are proposed by using the lowest dose that can achieve ≥90% PTA for AUC24/MIC of 98.9 at an MIC of ≤32 mg/L (EUCAST v.13 susceptibility breakpoint for Enterobacterales). For patients with normal kidney function (CLCR 91-120 mL/min), a dosage of 15 g/day is suggested. This regimen achieved 97.1% CFR against E. coli, whereas CFR was 72.9% for K. pneumoniae and 76.7% for P. aeruginosa. CONCLUSIONS: A fosfomycin dosage of 15 g/day with adjustment according to kidney function provided high PTA and CFR when treating E. coli. This dosage is lower than that used in current practice and may improve tolerability. Higher dosages may be needed for P. aeruginosa; however, safety data are limited.

[Antibacterial prophylaxis with fosfomycin at the time of the urethral catheter removal after radical prostatectomy (prospective randomized trial)].

AIM: To evaluate the effect of antibacterial prophylaxis using oral fosfomycin during the removal of a urethral catheter after radical prostatectomy on the development of urinary tract infection, severity of leukocyturia and bacteriuria, as well as the severity of lower urinary tract symptoms. MATERIALS AND METHODS: A single-center, non-blind, prospective, randomized controlled trial was carried out. The main group included 40 patients, and the control group included 37 patients. In the group 1, patients received two doses of oral fosfomycin, 3 g, namely in the evening on the day of catheter removal (the first dose) and 48 hours after catheter removal (the second dose). In the group 2, patients did not receive any antibacterial prophylaxis after urethral catheter removal. The endpoints of the study were confirmed episodes of urinary tract infection within 1 month after removal of the urethral catheter, leukocyturia and bacteriuria in urinalysis/urine culture) and severity of the lower urinary tract symptoms assessed by IPSS questionnaire. RESULTS: In the group 2, urinary tract infection was noted in 17.1%, while in the group 2 only in 2.6% of patients (p=0.032). Leukocyturia and bacteriuria were significantly less common in the group receiving antibacterial prophylaxis with fosfomycin (18.4% vs. 48.6%, respectively; p=0.006). Positive urine culture was observed in 7.9% vs. 25.7%, respectively (p=0.035). Four weeks after removal of the urethral catheter, the average IPSS score was significantly higher in the group 2 (13.2 vs. 9.5 points; p=0.002). There were no cases of allergic reaction and pseudomembranous colitis associated with C. difficile in both groups. Diarrhea cured with sorbents was noted in 2 patients (5.2%) in fosfomycin group. CONCLUSION: Antibacterial prophylaxis using two oral doses of fosfomycin 3 g on the day of urethral catheter removal and 48 hours after catheter removal after radical prostatectomy appears to be an effective scheme that reduces the incidence of urinary tract infection and the severity of lower urinary tract symptoms, and is characterized by a minimal risk of adverse events. It is necessary to carried out further research and develop clear recommendations for antibacterial prevention in urological interventions requiring prolonged urethral catheterization.

Intravenous fosfomycin in combination regimens as a treatment option for difficult-to-treat infections due to multi-drug-resistant Gram-negative organisms: A real-life experience.

AIM: To investigate the efficacy of intravenous (IV) fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) acute and subacute infections with multi-drug-resistant (MDR) Gram-negative bacteria (GNB), and risk factors associated with 90-day mortality. METHODS: A retrospective, observational, monocentric study enrolled patients treated with IV fosfomycin in combination regimens (≥72 h) for proven DTT-MDR-GNB infection. Multi-variate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving fosfomycin was performed to control for confounding factors. RESULTS: In total, 70 patients were included in this study: 54.3% had carbapenem-resistant isolates, 31.4% had ceftazidime/avibactam-resistant isolates and 28.6% had ceftolozane/tazobactam-resistant isolates. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), osteomyelitis (17.1%) and intra-abdominal infections. All-cause 30- and 90-day mortality were 15.7% and 31.4%, respectively (18.9% and 50% considering acute DTT-MDR-GNB infections alone). Relapse at 30 days occurred in 22.9% of cases (29% with emergence of fosfomycin resistance). Mortality at 90 days was independently associated with septic shock and ceftolozane/tazobactam resistance. The relationship between resistance to ceftolozane/tazobactam and 90-day mortality was confirmed to be significant after adjustment by propensity score analysis (hazard ratio 5.84, 95% confidence interval 1.65-20.68; P=0.006). CONCLUSIONS: Fosfomycin seems to be a promising salvage, combination treatment in DTT-MDR-GNB infections. Resistance to ceftolozane/tazobactam seems to be independently associated with treatment failure. Randomized clinical trials focusing on pathogen and infection sites are needed urgently to demonstrate the superiority of fosfomycin in combination with other agents for the resolution of DTT-MDR-GNB infections.

Investigation of In-vitro Efficacy of Intravenous Fosfomycin in Extensively Drug-Resistant Klebsiella pneumoniae Isolates and Effect of Glucose 6-Phosphate on Sensitivity Results.

BACKGROUND: The aim of this study was to determine the in vitro efficacy of intravenous (IV) fosfomycin against extensively drug-resistant Enterobacterales strains and the effect of glucose 6-phosphate (G6-P) on sensitivity results. MATERIAL METHOD: Thirty-two extensively drug-resistant Klebsiella pneumonia strains were included in the study. Detection of the carbapenemase genes was performed using the Gene-Xpert® System Carba R® kit. Susceptibility of IV fosfomycin was assessed using the agar dilution method. The agar dilution method was repeated using Muller-Hinton Agar medium without G6-P to assess the effect of G6-P on sensitivity results. RESULTS: All strains in the study produced carbapenemases and were resistant to all drugs tested, including carbapenems, piperacillin-tazobactam, ceftriaxone, and ceftazidime. Fosfomycin resistance was detected in 3 (9.3%) strains. When the sensitivity test was repeated without G6-P, fosfomycin resistance was detected in 82.7% of the fosfomycin-susceptible strains. The Gene-Xpert® System showed NDM-1 in 46.8%, OXA-48 in 18.7%, KPC in 3.1%, and NDM-1 + OXA-48 in 21.8% of the strains. OXA-48 was detected in one of the resistant strains, and none of the viable genes were detected in two of the resistant strains. CONCLUSION: This study shows that IV fosfomycin is a potentially important treatment alternative for infections caused by common resistant strains. Accurate results may not be obtained unless G6-P is used in the agar dilution method for in vitro susceptibility studies of fosfomycin.

Fosfomycin therapeutic drug monitoring in real-life: development and validation of a LC-MS/MS method on plasma samples.

Individualization of fosfomycin dosing based on therapeutic drug monitoring (TDM) of plasma concentrations could reduce drug-related adverse events and improve clinical outcome in complex clinical conditions. Quantification of fosfomycin in plasma samples was performed by a rapid ultraperformance liquid chromatography mass spectrometry method. Sample preparation involved protein precipitation with [13C3]-fosfomycin benzylamine salt as internal standard. The calibration curve ranged from 2 to 800 mg/L. Within- and between-day precision and accuracy, sensitivity, selectivity, dilution integrity, recovery were investigated and the results met the acceptance criteria. In patients, multiple drug dosing (every 6 or 8 hours) or in continuous administration were adopted, resulting in a large interpatient variability in drug concentrations (from 7.4 mg/L and 644.6 mg/L; CV: 91.1%). In critical care patient setting TDM can represent an important tool to identify the best fosfomycin dosing in single patients, taking into consideration clinical characteristics, infection sites and susceptibility of the treated pathogens.

Síndrome de intolerancia a múltiples medicamentos / Syndrome of intolerance to multiple medicines

El síndrome de intolerancia a múltiples medicamentos (MDIS, por sus siglas en inglés) se caracteriza por la intolerancia a dos o más medicamentos no relacionados. Tiene una prevalencia baja y es común en pacientes con polifarmacia. A pesar de que las reacciones adversas a los medicamentos son muy frecuentes, es raro que los pacientes debuten con este síndrome, el cual tiene implicaciones clínicas de leves a graves que afectan su vida; de acuerdo con esto varían el abordaje y su manejo. La sintomatología presentada varía desde síntomas gastrointestinales como reflujo gastroesofágico, dolores musculares y cefalea, hasta síntomas cutáneos; estos son los más frecuentes, tales como urticaria y erupciones maculopapulares o presentaciones menos comunes como el síndrome de Stevens-Johnson. El MDIS es causado por una amplia variedad de fármacos; por ello el conocimiento del síndrome, así como un adecuado interrogatorio de los antecedentes del paciente, es necesario para realizar un diagnóstico oportuno e instaurar un manejo adecuado y preventivo, evitando reacciones adversas que pongan en riesgo su vida. Con los hallazgos del cuadro clínico en la paciente, y basados en los antecedentes alérgicos presentados anteriormente a diferentes medicamentos no relacionados entre ellos, más la presentación de un rash maculopapular generalizado posterior a la administración de trimetoprim/sulfametoxazol se realiza el diagnóstico de MDIS. Se decide cambiar de medicamento por fosfomicina, con una consecuente evolución favorable. (AU)

Retrospective evaluation of intravenous fosfomycin in multi-drug resistant infections at a tertiary care hospital in Lebanon.

INTRODUCTION: Fosfomycin has re-emerged as a possible therapeutic alternative for the treatment of resistant bacterial pathogens. Its main mechanism of action is the inhibition of the initial step of cell wall synthesis and is active against both Gram-positive and Gram-negative bacteria. However, its clinical effectiveness against multidrug resistant bacteria remains largely unknown. Therefore, we aim to evaluate the clinical and microbiological effectiveness of intravenous fosfomycin as well as its safety in a tertiary care teaching hospital in Lebanon. METHODOLOGY: This is a retrospective chart review of adult patients who had presented to the hospital and were treated with intravenous fosfomycin for at least 24 hours for any type of infection between 2014 and 2019. RESULTS: Among 31 episodes treated with intravenous fosfomycin, 68% had an overall favorable clinical response. In 84% of the episodes, fosfomycin was administered in combination with other antibiotics, commonly tigecycline. Of those with available cultures at end of therapy, 73% achieved microbiological success. No relapse was documented within 30 days of completion of therapy. In the episodes secondary to resistant pathogens, the rates of favorable clinical outcome and microbiological success at the end of therapy were 71% and 73%, respectively. Fosfomycin resistance developed in two cases and mild adverse events occurred in 65% of the episodes during the course of treatment. CONCLUSIONS: Fosfomycin is a safe and effective option in the treatment of multi-drug resistant infections. Nevertheless, careful stewardship is important to maintain its efficacy and to reduce the risk of selection of antimicrobial resistance.

Fosfomycin and nitrofurantoin: classic antibiotics and perspectives.

Antibiotics are essential molecules for the treatment and prophylaxis of many infectious diseases. However, drugs that combat microbial infections can become a human health threat due to their high and often indiscriminate consumption, considered one of the factors of antimicrobial resistance (AMR) emergence. The AMR crisis, the decrease in new drug development by the pharmaceutical industry, and reduced economic incentives for research have all reduced the options for treating infections, and new strategies are necessary, including the return of some traditional but "forgotten" antibiotics. However, prescriptions for these older drugs including nitrofurantoin and oral fosfomycin, have been based on the results of pioneer studies, and the limited knowledge generated 50-70 years ago may not be enough. To avoid harming patients and further increasing multidrug resistance, systematic evaluation is required, mainly for the drugs prescribed for community-acquired infections, such as urinary tract infections (UTI). Therefore, this review has the objective of reporting the use of two classic drugs from the nitrofuran and phosphonic acid classes for UTI control nowadays. Furthermore, we also explore new approaches used for these antibiotics, including new combination regimes for spectral amplification, and the prospects for reducing bacterial resistance in the fight against bacteria responsible for UTI.

Elimination of fosfomycin during dialysis with the Genius system in septic patients.

To assess fosfomycin (FOS) elimination in patients with sepsis and acute kidney injury (AKI) undergoing slow-extended daily dialysis (SLEDD) with the Genius system in a prospective observational study. After ethics committee approval ten patients with sepsis and AKI stage 3 underwent daily SLEDD sessions of eight hours. FOS was applied i.v. at doses of 3 × 5 g per day. FOS serum levels were measured pre- and post hemofilter before, during, and after SLEDD sessions, and instantaneous clearance was calculated. In five of the patients, we analyzed FOS levels after the first dose, in the other five patients serum levels were measured during ongoing therapy. FOS was eliminated rapidly via the hemofilter. FOS clearance decreased from 152 ± 10 mL/min (start of SLEED session) to 43 ± 38 mL/min (end of SLEDD session). In 3/5 first-dose patients after 4-6 h of SLEDD the FOS serum level fell below the EUCAST breakpoint of 32 mg/L for Enterobacterales and Staphylococcus species. In all patients with ongoing fosfomycin therapy serum levels were high and above the breakpoint at all times. FOS toxicity or adverse effects were not observed. FOS serum concentrations exhibit wide variability in critically ill patients with sepsis and AKI. FOS is eliminated rapidly during SLEDD. A loading dose of 5 g is not sufficient to achieve serum levels above the EUCAST breakpoint for common bacteria in all patients, considering that T > MIC > 70% of the dosing interval indicates sufficient plasma levels. We thus recommend a loading dose of 8 g followed by a maintenance dose of 5 g after a SLEDD session in anuric patients. We strongly recommend therapeutic drug monitoring of FOS levels in critically ill patients with AKI and dialysis therapy.

Physicochemical and Antimicrobial Properties of Thermosensitive Chitosan Hydrogel Loaded with Fosfomycin.

Thermosensitive chitosan hydrogels-renewable, biocompatible materials-have many applications as injectable biomaterials for localized drug delivery in the treatment of a variety of diseases. To combat infections such as Staphylococcus aureus osteomyelitis, localized antibiotic delivery would allow for higher doses at the site of infection without the risks associated with traditional antibiotic regimens. Fosfomycin, a small antibiotic in its own class, was loaded into a chitosan hydrogel system with varied beta-glycerol phosphate (ß-GP) and fosfomycin (FOS) concentrations. The purpose of this study was to elucidate the interactions between FOS and chitosan hydrogel. The Kirby Bauer assay revealed an unexpected concentration-dependent inhibition of S. aureus, with reduced efficacy at the high FOS concentration but only at the low ß-GP concentration. No effect of FOS concentration was observed for the planktonic assay. Rheological testing revealed that increasing ß-GP concentration increased the storage modulus while decreasing gelation temperature. NMR showed that FOS was removed from the liquid portion of the hydrogel by reaction over 12 h. SEM and FTIR confirmed gels degraded and released organophosphates over 5 days. This work provides insight into the physicochemical interactions between fosfomycin and chitosan hydrogel systems and informs selection of biomaterial components for improving infection treatment.

Fosfomycin in continuous or prolonged infusion for systemic bacterial infections: a systematic review of its dosing regimen proposal from in vitro, in vivo and clinical studies.

Fosfomycin (FOS) administered intravenously has been recently rediscovered for the treatment of systemic infections due to multidrug-resistant bacteria. Its pharmacokinetic properties suggest a time-dependent dosing schedule with more clinical benefits from prolonged (PI) or continuous infusion (CI) than from intermittent infusion. We revised literature concerning PI and CI FOS to identify the best dosing regimen based on current evidence. We performed a MEDLINE/PubMed search. Ninety-one studies and their pertinent references were screened. Seventeen studies were included in the present review. The activity of FOS against Gram-negative and Gram-positive bacteria was evaluated in fourteen and five studies, respectively. Six studies evaluated FOS activity in combination with another antibiotic. Daily dosing of 12, 16, 18 or 24 g, administered with different schedules, were investigated. These regimens resulted active against the tested isolates in most cases. Emergence of resistant isolates has been shown to be preventable through the coadministration of another active antibiotic. FOS is a promising option to treat systemic infections caused by multidrug-resistant bacteria. Coadministration with another active molecule is required to prevent the emergence of resistant bacterial strains. The results of our review suggest that a therapeutic regimen including a loading dose of FOS 8 g followed by a daily dose of 16 g or 24 g CI could be the best therapeutic approach for patients with normal renal function. The dosing regimens in patients with renal insufficiency and CI or PI superiority compared with intermittent infusion in clinical settings should be further investigated.

Evaluation Strategies for Triple-Drug Combinations against Carbapenemase-Producing Klebsiella Pneumoniae in an In Vitro Hollow-Fiber Infection Model.

Mounting antimicrobial resistance to carbapenemase-producing Klebsiella pneumoniae (CPKP) highlights the need to optimize currently available treatment options. The objective of this study was to explore alternative dosing strategies that limit the emergence of resistance to preserve the utility of last-line antibiotics by: (i) evaluating the pharmacodynamic (PD) killing activity of simulated humanized exposures to monotherapy and two-drug and three-drug combinations against CPKP bacterial isolates with different resistance mechanisms; and (ii) optimizing polymyxin B (PMB) exposure simulated in the three-drug combination regimens to maximize the killing activity. Two CPKP clinical isolates (BAA2146 (NDM-1) and BRKP76 (KPC-2)) were evaluated over 168 hours using a hollow-fiber infection model simulating clinically relevant PMB, fosfomycin, and meropenem dosing regimens. PMB-based three-drug combinations were further optimized by varying the initial exposure (0-24 hours) or maintenance dose received over the duration of treatment. The area under the bacterial load-versus-time curve (AUCFU) was used to determine PD activity. Overall reductions in PMB exposure ranged from 2 to 84%. BAA2146 and BRKP76 had median (range) AUCFUs of 11.0 (10.6-11.6) log10  CFU hour/mL and 7.08 (7.04-11.9) log10 CFU hour/mL, respectively. The PMB "front loaded" 2.5 mg/kg/day + 0.5 mg/kg maintenance dose in combination with meropenem and fosfomycin was a promising regimen against BRKP76, with an overall reduction in PMB exposure of 56% while still eradicating the bacteria. Tailored triple-combination therapy allows for the optimization of dose and treatment duration of last-line agents like PMB to achieve adequate drug exposure and appropriate PD activity while minimizing the emergence of resistance.

Pharmacodynamic Analysis of Meropenem and Fosfomycin Combination Against Carbapenem-Resistant Acinetobacter baumannii in Patients with Normal Renal Clearance: Can It Be a Treatment Option?

Background and Objective: Combination therapy may be a treatment option against carbapenem-resistant Acinetobacter baumannii (CR-AB) infections. In this study, we explored the utility of fosfomycin in combination with meropenem (FOS/MEM) against CR-AB isolates. Materials and Methods: Screening of synergistic activity of FOS/MEM was performed using the checkerboard assay. A pharmacokinetic/pharmacodynamic analysis was performed for various FOS/MEM regimens using Monte Carlo simulations. Results: The minimum inhibitory concentration (MIC) required to inhibit the growth of 50% of the isolates (MIC50) and MIC required to inhibit the growth of 90% of the isolates (MIC90) of FOS and MEM were reduced fourfold and twofold, respectively. The combination was synergistic against 14/50 isolates. No antagonism was observed. Sixteen out of fifty isolates had MEM MICs of ≤8 mg/L when subjected to combination therapy, compared to none with monotherapy. Forty-one out of 50 isolates had FOS MICs of ≤128 mg/L when subjected to combination therapy, compared to 17/50 isolates with monotherapy. The cumulative fraction response for MEM and FOS improved from 0% to 40% and 40% to 80%, with combination therapy, respectively. Conclusions: Addition of MEM improved the in vitro activity of FOS against the CR-AB isolates. FOS/MEM could be a plausible option to treat CR-AB for a small fraction of isolates.

Pharmacotherapeutic advances for recurrent urinary tract infections in women.

INTRODUCTION: Treatment of recurrent Urinary tract infections (UTIs) has become challenging because of the dramatic increase in the rates of recurrent infection andof multidrug-resistant (MDR) infections. AREAS COVERED: The authors review recurrent UTIs(rUTI) management in women. EXPERT OPINION: Continuous or post-coital prophylaxis with low-dose antimicrobials or intermittent self-treatment has all been demonstrated to be effective in managing rUTIs in women. Intravaginal estrogen therapy , shows potential toward preventing rUTI. Oral vaccine Uro-Vaxom seems to reduce the number of UTIs. There is evidence that other therapies (e.g. cranberry, Methenamine hippurate, oral D-mannose) may decrease the number of symptomatic UTIs. The treatment of CRE-UTIs is focused on a colistin backbone. Carbapenems are considered first-line agents for UTIs caused by ESBL, but their use is associated with increased MDR. The usage of non-carbapenem for the treatment of ESBL UTIs is necessary. Cefepime, Piperacillin-Tazobactam, Ceftolozane-Tazobactam, and Ceftazidime-Avibactam are justified options. Oral therapy with Pivmecillinam, Fosfomycin, and Nitrofurantoin can be used against uncomplicated UTIs due to ESBL infection.

Intravenous fosfomycin for the treatment of patients with central nervous system infections: evaluation of the published evidence.

INTRODUCTION: Central nervous system (CNS) infections have considerable morbidity and mortality. Fosfomycin is a broad spectrum bactericidal antibiotic with favorable pharmacokinetic properties and low toxicity, satisfactory penetration in the cerebrospinal fluid and is authorized for the treatment of bacterial meningitis. AREAS COVERED: The objective of this analysis was to evaluate the available data regarding the effectiveness and safety of intravenous fosfomycin for the treatment of CNS infections. Thirty-two relevant publications were identified. Data from 224 patients who received intravenous fosfomycin as treatment for CNS infections were evaluated. Overall, 93.8% of patients were cured from the infection. Staphylococcus was the most frequent pathogen; Streptococcus pneumoniae, Neisseria meningitidis, and several other microbial agents, including multi-drug resistant and extensively drug-resistant bacteria, were also implicated. Fosfomycin was given as part of a combination treatment in the vast majority of the patients. The dosage of fosfomycin ranged between 4 g and 24 g per day; a regimen with 14-16 g per day was used in the majority of the cases. Fosfomycin was generally well tolerated. EXPERT OPINION: The evaluation of the published evidence suggests that fosfomycin may be beneficial in the treatment of patients with CNS infections.

Evaluation of fosfomycin combined with vancomycin against vancomycin-resistant coagulase negative staphylococci.

The pathogenic potential of coagulase-negative staphylococci (CoNS) is increasingly recognized worldwide. The aim of the present study was to evaluate different combinations of fosfomycin (FOS) with vancomycin (VAN) or oxacillin (OXA) against vancomycin-resistant clinical isolates of CoNS. Characterization of VAN resistance in selected isolates was also sought. Antibiotic susceptibility of isolates was tested by disc diffusion method, MICs of antibiotics were determined by the agar dilution method, and fosfomycin combinations were evaluated by a time-kill assay according to the guidelines of the CLSI. Moreover, oxacillin and glycopeptides (vancomycin and teichoplanin) resistances were also characterized phenotypically and genotypically in this study. Out of 258 staphylococci, 52 were CoNS (20.2%). All isolates were multidrug resistant with 75% (n = 39) oxacillin-resistant, most of them with oxacillin MIC levels of >32 mg/L. Moreover, vancomycin non-susceptibility was observed in 46.2% (n = 24) of the tested isolates with MIC range of 4-32 mg/L. Identification of selected isolates revealed that S. epidermidis was the most abundant among tested CoNS, followed by S. hominis, S. saprophyticus, and interestingly S. caseolyticus. Furthermore, Synergistic and bactericidal effects of FOS + VAN combination were observed in 3 of 9 isolates after 6 h of treatment and in all studied isolates at 24 h. On the other hand, FOS + OXA combinations were ineffective. This study provides evidence that fosfomycin combination with vancomycin could be considered as a therapeutic alternative for CoNS infections. It also sheds some light on the possible emergence of the otherwise harmless bacterium S. caseolyticus as a human pathogen.

Oral Fosfomycin Efficacy with Variable Urinary Exposures following Single and Multiple Doses against Enterobacterales: the Importance of Heteroresistance for Growth Outcome.

Oral fosfomycin trometamol is licensed as a single oral dose for the treatment of uncomplicated urinary tract infections, with activity against multidrug-resistant uropathogens. The impact of interindividual variability in urinary concentrations on antimicrobial efficacy, and any benefit of giving multiple doses, is uncertain. We therefore performed pharmacodynamic profiling of oral fosfomycin, using a dynamic bladder infection in vitro model, to assess high and low urinary exposures following a single oral dose and three repeat doses given every 72 h, 48 h, and 24 h against 16 clinical isolates with various MICs of fosfomycin (8 Escherichia coli, 4 Enterobacter cloacae, and 4 Klebsiella pneumoniae isolates). Baseline fosfomycin high-level-resistant (HLR) subpopulations were detected prior to drug exposure in half of the isolates (2 E. coli, 2 E. cloacae, and 4 K. pneumoniae isolates; proportion, 1 × 10-5 to 5 × 10-4% of the total population). Fosfomycin exposures were accurately reproduced compared to mathematical modeling (linear regression slope, 1.1; R2, 0.99), with a bias of 3.8% ± 5.7%. All 5/5 isolates with MICs of ≤1 µg/ml had no HLR and were killed, whereas 8/11 isolates with higher MICs regrew regardless of exposure to high or low urinary concentrations. A disk diffusion zone of <24 mm was a better predictor for baseline HLR and regrowth. Administering 3 doses with average exposures provided very limited additional kill. These results suggest that baseline heteroresistance is important for treatment response, while increased drug exposure and administering multiple doses may not be better than standard single-dose fosfomycin therapy.

The plasma pharmacokinetics of fosfomycin and metronidazole after intraperitoneal administration in patients undergoing appendectomy for uncomplicated appendicitis.

We aimed to investigate the pharmacokinetics of fosfomycin and metronidazole after intraperitoneal administration of the combination of fosfomycin and metronidazole in patients undergoing laparoscopic appendectomy for uncomplicated appendicitis. We included eight otherwise healthy men undergoing laparoscopic appendectomy. The trial treatment was administered at the end of the surgical procedure and left in the abdominal cavity. Trial drugs consisted of 4 g fosfomycin and 1 g metronidazole in a total volume of 500.2 mL. Blood samples were collected prior to and ½, 1, 2, 4, 8, 12 and 24 h after administration. High-performance liquid chromatography-mass spectrometry was used for the measurement of plasma concentrations, and pharmacokinetic calculations were undertaken. Antimicrobial susceptibility testing was undertaken on isolates from intraoperatively collected specimens. The median maximal concentration for fosfomycin in plasma was 104.4 mg/L, median time point for the maximal concentration was 1.5 h, median half-life 3.0 h, and median area under the curve 608 mg*h/L. The median maximal concentration for metronidazole in plasma was 13.6 mg/L, median time point for the maximal concentration was 2.0 h, median half-life 7.3 h, and median area under the curve was 164 mg*h/L. All aerobic bacteria were susceptible to fosfomycin, and all anaerobes were susceptible to metronidazole. Plasma concentrations of fosfomycin and metronidazole were in line with concentrations reported from pharmacokinetic studies after intravenous administration and were within therapeutic ranges.